Graphical Abstract:

Abstract:

We have recently developed three antitrypanosomal leads that feature a unit of huprine or
(6-chloro-)tacrine linked to a 8-cyanooctyl side chain, which, unfortunately, exhibit very potent (low
nanomolar) acetylcholinesterase (AChE) inhibitory activity, which might lead to unwanted cholinergic
side-effects. Because huprine and tacrine moieties impart high acetylcholinesterasic potency, we have
explored their replacement by alternative heteroaromatic systems (thiazolylbenzamido, quinoxalinecarboxamido,
benzimidazolecarboxamido, and benzothiazolylamino moieties), while retaining the 8-
cyanooctyl side chain. These structural modifications led to the desired drop in AChE inhibitory activity
(low micromolar), albeit at the expense of the antitrypanosomal potency. However, despite the
lower AChE inhibitory activity of the novel compounds compared to that of the initial leads, their potency
is comparable to that of some AChE inhibitors currently approved for Alzheimer's disease (AD)
treatment. They are brain permeable and less lipophilic than the leads, thereby emerging as interesting
novel hits for future AChE inhibitor-based AD drug discovery programs.

Affiliation:Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, Department of Pharmacology, Therapeutics and Toxicology, Institute of Neurosciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Department of Pharmacology, Therapeutics and Toxicology, Institute of Neurosciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona

Abstract:We have recently developed three antitrypanosomal leads that feature a unit of huprine or
(6-chloro-)tacrine linked to a 8-cyanooctyl side chain, which, unfortunately, exhibit very potent (low
nanomolar) acetylcholinesterase (AChE) inhibitory activity, which might lead to unwanted cholinergic
side-effects. Because huprine and tacrine moieties impart high acetylcholinesterasic potency, we have
explored their replacement by alternative heteroaromatic systems (thiazolylbenzamido, quinoxalinecarboxamido,
benzimidazolecarboxamido, and benzothiazolylamino moieties), while retaining the 8-
cyanooctyl side chain. These structural modifications led to the desired drop in AChE inhibitory activity
(low micromolar), albeit at the expense of the antitrypanosomal potency. However, despite the
lower AChE inhibitory activity of the novel compounds compared to that of the initial leads, their potency
is comparable to that of some AChE inhibitors currently approved for Alzheimer's disease (AD)
treatment. They are brain permeable and less lipophilic than the leads, thereby emerging as interesting
novel hits for future AChE inhibitor-based AD drug discovery programs.